Role of the pro-longevity FOXO transcription factors in cognitive function

Cognitive function, in particular memory, declines during aging. This cognitive decline may not only be due to the depletion of the NSC pool, but also to defects in synaptic plasticity and neuronal connectivity. Intriguingly, the most recently discovered FOXO isoform in mammals, FOXO6, is enriched in adult hippocampal neurons, in a region critical for learning and memory. However, the role of this brain-specific FoxO isoform in the adult organism had never been tested. We have recently made a crucial step in understanding the importance of FOXO6 in learning and memory in vivo. By generating mice with a deletion in the FOXO6 gene, we found that FoxO6 is necessary for the retrieval of memories, but dispensable for learning. Using a genome-wide approach, we identified the gene expression program regulated by FOXO6 in the hippocampus before and after learning. The FOXO family of transcription factors was previously known for its role in longevity, tumor suppression, and adult stem cells. Our study identifies a new role for the brain-enriched FOXO transcription factor in memory and synaptic function, which has pivotal implications for the connection between aging and cognitive function.